tbuckley/cabot-search huggingface dataset:
Abstract 3863: Aminoflavone confers activity against aromatase inhibitor-resistant breast cancer cells in part via miR125b2-3p restoration
Authors: Eileen J. Brantley, Nicole Mavingire, Salma Khan, Gayathri Nagaraj, Shawnee Angeloni, Charles Wang, Ubaldo Soto
Journal: Cancer Research (2023)

Abstract Aromatase inhibitor therapy is the most crucial adjuvant treatment option for postmenopausal women with hormone receptor-positive (HR+) non-metastatic breast cancer. However, up to 30% of these patients will experience relapse due in part to aromatase inhibitor resistance. We recently identified miR125b2-3p as a putative tumor suppressor in HR+ breast cancer. We also found that small molecule Aminoflavone (AF) induces miR125b2-3p expression in HR+ breast cancer cells. In the current study, we hypothesized that AF confers anticancer actions in breast cancer cells resistant to aromatase inhibitors via miR125b2-3p reactivation. Using the Alamar Blue and colony forming assays, we discovered that AF demonstrated anticancer activity in estrogen-deprived resistant (EDR) cells designed to mimic aromatase inhibitor resistance. AntagomiR125b2-3p enhanced, while miR125b2-3p mimics diminished colony formation of EDR cells. AF-mediated suppression of colony formation in EDR cells was attenuated during co-treatment with antagomiR125b2-3p and was enhanced during co-treatment with miR125b2-3p mimics. Both miR125b2-3p mimics and AF suppressed EDR cell migration. AntagomiR125b2-3p counteracted AF-mediated suppression of cell migration. Our in silico profiling studies identified the alpha6-integrin, a mediator of breast cancer stem cell activity and metastasis, as one miR-125b2-3p target. Immunohistochemistry of patient tumor samples revealed that alpha 6-integrin protein expression intensified following relapse on the aromatase inhibitor anastrozole. MCF-7 cells transfected to overexpress the alpha 6-integrin were less responsive to anastrozole than those transfected with empty vector. These data suggest that AF restores the tumor suppressor function of miR125b2-3p to inhibit the alpha 6-integrin and confer activity against aromatase inhibitor-resistant breast cancer. Citation Format: Eileen J. Brantley, Nicole Mavingire, Salma Khan, Gayathri Nagaraj, Shawnee Angeloni, Charles Wang, Ubaldo Soto. Aminoflavone confers activity against aromatase inhibitor-resistant breast cancer cells in part via miR125b2-3p restoration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3863.
Abstract 6482: CLDN18.2 expression is associated with clinicopathological features and prognosis of Chinese patients with digestive system cancers: a retrospective analysis
Authors: Chong XiaoYi, Changsong Qi, Jifang Gong, Miao Zhang, Mingyang Ma, keren Jia, Ting Zhou, Li Jian, Zhi Peng, Jun Xiao, Xiaohui Peng, Zhen Liu, Zonghai Li, Xiaotian Zhang, Lin Shen
Journal: Cancer Research (2023)

Abstract Importance: CLDN18.2 was a promising therapeutic target in solid tumors, whereas the clinicopathological features of Chinese CLDN18.2-positive cancer patients were rarely elucidated. Objective: This study aimed to explore the association between CLDN18.2 expression and clinicopathological features of Chinese patients with CLDN18.2-positive digestive system cancers. Methods: This retrospective study included digestive system cancer patients from June 2019 to April 2021 who were screened for two clinical trials of CT041 (an anti-CLDN18.2 CAR-T cell, NCT03874897, and NCT04581473), which were initiated at our center. Results: A total of 875 digestive system cancer patients were included. CLDN18.2 expression was observed in 73.1% GC patients, 61.8% pancreatic cancer (PC) patients, 10.6% colorectal cancer (CRC) patients, and 65.6% biliary tract carcinoma (BTC) patients. In GC, CLDN18.2 expression was associated with age, sex, and Lauren phenotype (all P&amp;lt;0.01). CLDN18.2-positive GC patients had a higher incidence of uterine adnexa metastasis (6.4% vs. 20.8%, P&amp;lt;0.001), and a lower incidence of liver metastasis (22.2% vs. 35.7%, P&amp;lt;0.001). In PC, CLDN18.2-positive cases had a higher proportion of tumors with moderate/high differentiation (46.1% vs. 19.0%, P&amp;lt;0.001), compared with CLDN18.2-negative patients. Additionally, compared with CLDN18.2-negative patients, the proportion of right colon cancer was higher in CLDN18.2-positive patients (40% vs. 18.1%, P=0.028). Conclusions: The results of this study suggested that CLDN18.2-positive tumors had unique clinicopathological features, which provided a theoretical basis for the treatment of CLDN18.2 positive tumors. Citation Format: Chong XiaoYi, Changsong Qi, Jifang Gong, Miao Zhang, Mingyang Ma, keren Jia, Ting Zhou, Li Jian, Zhi Peng, Jun Xiao, Xiaohui Peng, Zhen Liu, Zonghai Li, Xiaotian Zhang, Lin Shen. CLDN18.2 expression is associated with clinicopathological features and prognosis of Chinese patients with digestive system cancers: a retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6482.
Abstract 2916: CAR-NK cells generated with CAR-RNA-LNP express high cytotoxic activity against tumor cells
Authors: Vita M. Golubovskaya, Jinying Sun, John Sienkiewicz, Yanwei Huang, Hua Zhou, Gongping Deng, Hizkia Harto, Shirley Xu, Robert Berahovich, Lijun Wu
Journal: Cancer Research (2023)

Abstract NK (natural killer) cells have several advantages compared to T cells such as no cytokine release syndrome (CRS), neurotoxicity and GVHD in allogenic setting to kill tumors. We developed CAR-NK platform using RNA-LNP (lipid-nanoparticles) technology. High expansion of NK cells (up to 2000-fold) was achieved using K562 feeder cells with stable expression of 4-1BBL and IL-21. We showed efficient encapsulation of BCMA and CD19-CAR RNA into LNP that resulted in up to 99% expression of CAR+ CD56+ NK cells after transfection. The BCMA-CAR-NK cells more effectively than NK cells killed MM1S, H929 and RPMI8226 multiple myeloma cells and secreted IFN-gamma in a dose-dependent manner. In addition, frozen BCMA-CAR-NK cells were viable and expressed similar cytotoxic activity to not frozen expanded CAR-NK cells. In addition, frozen-thawed BCMA-CAR-NK cells showed 93% CAR expression at 24 hours post-thaw which remained &amp;gt;70% at 48 hours post-thaw. In a similar way, CD19-CAR-NK cells generated with CD19-CAR-LNP killed CD19-positive Raji and Daudi target cells and secreted high level of IFN-gamma. This, frozen/thawed CAR-NK cells demonstrated high in vitro cytotoxic activity against target cells. Manufacturing of NK cells using G-Rex system resulted in 1862-fold expansion at day 13 and 2450-fold expansion of 97% CD56+ NK cells at day 14. Transfection of BCMA-CAR RNA-LNP into 13 day expanded NK cells resulted in 95% BCMA-CAR-NK positive cells. Thus, CAR-NK cells generated with RNA-LNP technology can be used in future pre-clinical studies. Citation Format: Vita M. Golubovskaya, Jinying Sun, John Sienkiewicz, Yanwei Huang, Hua Zhou, Gongping Deng, Hizkia Harto, Shirley Xu, Robert Berahovich, Lijun Wu. CAR-NK cells generated with CAR-RNA-LNP express high cytotoxic activity against tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2916.
Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy
Authors: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra
Journal: Cancer Research (2023)

Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches. In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4432.
Abstract 3162: Genome-scale metabolic modeling suggests novel molecular targets in ER-positive breast cancer
Authors: Zachary B. Mudge, Kristof Kovacs, Melissa L. Kemp, Sunil S. Badve, Yesim Gokmen-Polar
Journal: Cancer Research (2023)

Abstract High expression of the epithelial splicing regulatory protein 1 (ESRP1) is correlated with poor prognosis in estrogen receptor positive (ER+) breast cancer and acquired resistance to tamoxifen/endocrine therapies. Our previous study revealed a novel functionality of ESRP1 in metabolic dysregulation by affecting lipid metabolism and oxidoreductase processes. To further understand how metabolic programming is affected by ESRP1 expression and identify novel therapeutic targets, we developed systems biology models to explore ER+ breast cancer metabolism. Flux balance analysis (FBA) is a computational approach to predict steady-state fluxes through metabolic reactions by posing cellular “objectives” such as maximization of biomass, ATP, or minimization of reactive oxygen species that reflect selective pressures posed by the tumor microenvironment or therapeutic insults. Our custom FBA pipeline leverages transcriptomic data, mutation information, and thermodynamic constraints to generate personalized genome-scale metabolic models. In this study, 100 ESRP1-high and 100 ESRP1-low tumors from the TCGA Breast Cancer Invasive Carcinoma dataset were simulated and compared; in a secondary analysis, we simulated metabolic rerouting of tamoxifen-resistant LCC2 cells and fulvestrant-resistant LCC9 cells upon ESRP1 knockdown. The intersection of statistically significant (p &amp;lt; 0.05) reactions that were altered in both the TCGA and cell line contexts suggested that changes in eicosanoid metabolism and androgen and estrogen synthesis pathways are highly involved in ESRP1's role in breast cancer prognosis and resistance to endocrine therapies. Eicosanoid-utilizing enzymes are consistently altered between the ESRP1-low and high conditions; Hematopoietic prostaglandin D synthase (HPGDS), prostaglandin I2 synthase (PTDIS), and thromboxane A synthase 1 (TBXAS1) are druggable. Furthermore, reactions associated with cytosolic and lysosomal 4-hydroxy-17beta-estradiol production, catalyzed by the enzymes myeloperoxidase, lactoperoxidase, and peroxiredoxin 6, also emerged as consistently altered across the groups. The findings from this methodology have suggested novel metabolic targets to overcome tamoxifen/endocrine therapy resistance in ER+ breast cancer. Experimental validation of these targets is currently underway. Citation Format: Zachary B. Mudge, Kristof Kovacs, Melissa L. Kemp, Sunil S. Badve, Yesim Gokmen-Polar. Genome-scale metabolic modeling suggests novel molecular targets in ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3162.
Abstract 1151: CD6 isoforms improve CAR T cell fitness
Authors: Jessica S. Morris, Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, Nabil Ahmed
Journal: Cancer Research (2023)

Abstract The ability of chimeric antigen receptor (CAR) T cells to initiate and sustain an effective immune response entails a delicate balance between T-cell activation and deactivation and is key for complete tumor elimination. CD6 is a co-receptor that fine-tunes T cell receptor signal strength through a unique dual function intracellular domain. CD6 is alternatively spliced, creating isoforms that lack distinct regions which interact with activating or inhibitory adapter proteins, thereby delivering inhibitory or activating signals, respectively. We hypothesized that CAR T cell fitness, namely their ability to sustain their effector function, can be achieved by using alternatively spliced CD6 isoforms which lack exons responsible for inhibitory signaling. First, we discovered that overexpression of the canonical full-length CD6 molecule, isoform CD6A, resulted in marginal improvement of CAR T cell function, while its deletion using CRISPR/Cas9 depressed the antitumor CAR T cell functionality. This supported a net stimulatory role for CD6 in CAR T cell function. To study their effect on cellular fitness, we then synthesized and overexpressed known alternatively spliced cytoplasmic isoforms CD6B, CD6C, CD6D, CD6E, and CD6F on CAR T cells and, noted a significant tendency towards preserving the CAR T cell naïve and central memory compartments, upon tumor encounter. Overexpression of isoform CD6F, which lacks exon 9, and to a lesser extent isoforms CD6C and CD6E enhanced the short- and long-term cytotoxicity of HER2 and CD19 targeting CAR T cells when compared to CAR T cells alone or CAR T cells overexpressing, CD6A. Despite exhibiting a lower proliferation index, and lower CAR CD3ζ phosphorylation at rest, CD6F CAR T cells secreted significantly higher concentrations of the Th1 cytokine, IFN-γ, and mediated more sustained in vitro cytotoxicity long-term, with more complete elimination of large tumor cell loads. Lastly, in an orthotopic model of human glioblastoma, the adoptive transfer of CD6F HER2 CAR T cells induced a more significant but also more sustained anti-glioma effect that translated into a significant survival advantage for experimental animals. Our data support that the overexpression of the alternatively spliced CD6 isoforms improves CAR T cell fitness resulting in superior antitumor activity both in vitro and in vivo. Citation Format: Jessica S. Morris, Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, Nabil Ahmed. CD6 isoforms improve CAR T cell fitness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1151.
Abstract 289: B7-H3 mediated metabolic reprogramming promotes small cell lung cancer progression
Authors: Mahek Fatima, Parvez Khan, Asad Ur Rehman, Md Arafat Khan, Shailendra Kumar Maurya, Aatiya Ahmad, Mohd Ali Zaidi, Shailendra Gautam, Subodh Lele, Surinder Kumar Batra, Mohd Wasim Nasser
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer. The overall survival rate of SCLC is dismal owing to early metastasis, chemoresistance, higher rate of recurrence, and lack of available treatment options. Although some immunotherapeutic drugs have been approved for SCLC, they are effective only in a small fraction of the patient population. This necessitates the quest to find promising vulnerabilities against SCLC. Bioinformatic analysis on SCLC data set in the backdrop of various immune checkpoint regulators revealed B7-H3 as a promising target. The bioinformatics data was recapitulated in SCLC cell lines and human SCLC tissues. To delineate the effects of B7-H3 targeting, we performed CRISPR-Cas9 mediated B7-H3 knockout in SCLC cell lines. B7-H3 knockout in SCLC cells showed a decrease in colony formation, migration, and wound healing properties. Our results suggest that deletion of B7-H3 decrease the functional activities and activation of oncogenic signaling pathways, such as Erk, Akt, and Stat3. Further, we assessed if B7-H3 regulates SCLC metabolism. Preliminary data showed that B7-H3 knockout in SCLC cells inhibits glucose uptake, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR), suggesting its role in SCLC metabolic reprogramming. Altogether, our data indicate that B7-H3 plays a crucial role in SCLC pathogenesis and could serve as a potential therapeutic target for SCLC. Citation Format: Mahek Fatima, Parvez Khan, Asad Ur Rehman, Md Arafat Khan, Shailendra Kumar Maurya, Aatiya Ahmad, Mohd Ali Zaidi, Shailendra Gautam, Subodh Lele, Surinder Kumar Batra, Mohd Wasim Nasser. B7-H3 mediated metabolic reprogramming promotes small cell lung cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 289.
Abstract 3265: Temozolomide combined with ipilimumab + nivolumab enhances T cell killing of MGMT-expressing, MSS colorectal cancer cells
Authors: Zenovia Gonzalez, Lindsey J. Carlsen, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is the third most frequently diagnosed cancer and third-deadliest cancer globally. Approximately 95% of patients with metastatic CRC have tumors that are microsatellite stable (MSS) and do not respond to immune checkpoint inhibitors (ICI). Results from the 2022 MAYA clinical trial suggest that the DNA-damaging agent temozolomide (TMZ), which is usually used to treat glioblastoma (GBM), sensitizes patients with MSS, MGMT-silenced CRC to ipilimumab + nivolumab ICI. The benefit of adding ipilimumab + nivolumab to TMZ and the impact of MGMT silencing remain unclear. Here, we aimed to determine in a controlled in vitro system if adding ICI to TMZ enhances T cell killing of MSS CRC cells. We also aimed to determine the role of MGMT in this response. MGMT protein expression was measured by western blot in CRC (n=4) and GBM (n=4) cell lines. Cell viability assays were conducted to measure sensitivity to TMZ. CRC and GBM cells were co-cultured with TALL-104 cells -/+ TMZ and -/+ ICI to measure TALL-104-mediated cell death. Western blot analysis indicated that CRC cells had significantly elevated MGMT expression as compared to GBM cells likely due to MGMT promoter methylation in GBM cells. In line with this, CRC cells were slightly more resistant to TMZ (IC50=100-150 µM) compared to GBM cells (IC50=10-90 µM) after five days of treatment. TMZ + ICI sensitized MGMT-expressing, MSS CRC cells to T cell killing. TMZ alone did not enhance T cell killing of MSS or MSI CRC cells but did enhance T cell killing of T98G GBM cells. Our results indicate that TMZ sensitizes MSS, MGMT-expressing CRC cells to ipilimumab + nivolumab ICI. Importantly, this suggests that TMZ-mediated sensitization to ipilimumab + nivolumab is independent of MGMT status and the patient cohort that may benefit TMZ + ipilimumab + nivolumab may be expanded to CRC patients with MGMT-expressing, MSS tumors. Citation Format: Zenovia Gonzalez, Lindsey J. Carlsen, Wafik S. El-Deiry. Temozolomide combined with ipilimumab + nivolumab enhances T cell killing of MGMT-expressing, MSS colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3265.
Abstract 1081: Co-targeting CK1epsilon and PIK3CB/p110beta to treat glioblastoma
Authors: Eileen Xu
Journal: Cancer Research (2023)

Abstract The purpose of this study is to determine whether co-inhibition of CK1epsilon and PIK3CB/p110β is an effective therapeutic treatment for Glioblastoma (GBM). GBM is the most common and malignant primary brain cancer in adults. GBM has a dismal prognosis of death within 6 months if left untreated, thus there is a clinically unmet need for new and effective treatments. CK1epsilon has been identified as a GBM survival kinase gene. CK1epsilon promotes growth of GBM cells by inhibiting β-catenin. However, blocking CK1epsilon alone fails to completely block tumor growth perhaps because β-catenin can be regulated by other kinases. PIK3CB/p110β is another GBM survival kinase gene which also acts upstream of β-catenin. As seen with CK1epsilon, blocking PIK3CB/p110β alone also fails to completely block tumor growth. It is possible that blocking either CK1epsilon or PIK3CB/p110β alone does not substantially activate β-catenin to induce massive GBM cell death, thus limiting their therapeutic efficacy as a single agent. It is therefore imperative to investigate if co-targeting CK1epsilon and PIK3CB/p110β yields a synergistic inhibitory effect on GBM cell growth. GBM cells were treated with either DMSO (control), IC261 (chemical inhibitor of CK1epsilon), AZD6482 (chemical inhibitor of PIK3CB/p110β), or both IC261 and AZD6482. Cell viability was measured using the MTS viability assay. Cell viability for the treatment groups were as follows: AZD6482 (88.81%), IC261 (66.78%), and combination of AZD6482+IC261 (42.59%). Statistical analysis of drug synergy using the Bliss independence model yielded an Excess Over Bliss score greater than 0%, indicating a synergistic effect. To further elucidate the mechanism of GBM cell death, immunoblotting will also be performed to detect β-catenin activity after inhibition of CK1epsilon and PIK3CB/p110β. Overall, preliminary results show that co-inhibition of CK1epsilon and PIK3CB/p110β with chemical inhibitors yields synergistic GBM cell death. Citation Format: Eileen Xu. Co-targeting CK1epsilon and PIK3CB/p110beta to treat glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1081.